Decline of increased risk donor offers increases waitlist mortality in paediatric heart transplantation

Background: Increased risk donors in paediatric heart transplantation have characteristics that may increase the risk of infectious disease transmission despite negative serologic testing. However, the risk of disease transmission is low, and refusing an IRD offer may increase waitlist mortality. We sought to determine the risks of declining an initial IRD organ offer. Methods and results: We performed a retrospective analysis of candidates waitlisted for isolated PHT using 20072017 United Network of Organ Sharing datasets. Match runs identified candidates receiving IRD offers. Competing risks analysis was used to determine mortality risk for those that declined an initial IRD offer with stratified Cox regression to estimate the survival benefit associated with accepting initial IRD offers. Overall, 238/1067 (22.3%) initial IRD offers were accepted. Candidates accepting an IRD offer were younger (7.2 versus 9.8 years, p < 0.001), more often female (50 versus 41%, p = 0.021), more often listed status 1A (75.6 versus 61.9%, p < 0.001), and less likely to require mechanical bridge to PHT (16% versus 23%, p = 0.036). At 1- and 5-year follow-up, cumulative mortality was significantly lower for candidates who accepted compared to those that declined (6% versus 13% 1-year mortality and 15% versus 25% 5-year mortality, p = 0.0033). Decline of an IRD offer was associated with an adjusted hazard ratio for mortality of 1.87 (95% CI 1.24, 2.81, p < 0.003). Conclusions: IRD organ acceptance is associated with a substantial survival benefit. Increasing acceptance of IRD organs may provide a targetable opportunity to decrease waitlist mortality in PHT.

Trends in survival from myeloma, 1990–2015: a competing risks analysis

Background Myeloma survival has greatly increased over past decades. We investigated trends in survival over time in New Zealand by age, ethnicity, and geography and thus examined potential inequalities among these population subgroups. Methods From data supplied by the New Zealand Ministry of Health, all new diagnoses of multiple myeloma (ICD-10 code C90) between 1990 and 2016 were extracted, as well as their matched mortality data. Cox’s proportional hazards regression and competing risks regression were used to estimate multivariable survival functions. Results Between 1 January 1990 and 1 December 2015, 6642 myeloma cases were registered by the New Zealand Cancer Registry. Although survival from myeloma increased substantially from 1990–1994 to 2010–2015, 5-year survival was still only about 60% in 2010–2015. The greatest improvement in survival was for people aged 60–69 years at diagnosis. Using Cox’s proportional hazards regression, Māori showed an increased risk of myeloma death but this was predominantly due to differences in competing risks among ethnic groups. Competing risks analysis found the greatest improvement in myeloma survival in Pacific Islanders, and in 2010–2015 Māori had better survival than other ethnicities. Myeloma survival improved significantly over time in all regional health authorities but in all time periods the Central and Southern regions had significantly poorer survival than the Midland region. Conclusions Improvements in myeloma survival have been unequal across subgroups and regions in New Zealand. Detailed information about utilization of chemotherapeutic agents and transplantation in New Zealand is not available. This information, as well as more detailed hematological data, is essential to further explore the relationships and reasons for differing myeloma survival in population subgroups of New Zealand.

Early empirical TB treatment in HIV-positive patients admitted to hospital in South Africa: an observational cohort study

Background Empirical TB treatment in HIV-positive inpatients is common and may undermine the impact of new diagnostics. We sought to describe empirical TB treatment and compare characteristics and outcomes with patients treated for TB after screening. Methods Retrospective observational cohort study of HIV-positive inpatients treated empirically for TB prior to TB screening. Data on clinical characteristics, investigations and outcomes were collected from medical records. Comparison cohorts with microbiologically-confirmed or empirical TB treatment after TB screening with Xpert MTB/RIF and urine lipoarabinomannan assays were taken from South African STAMP trial site. In-hospital mortality was compared using a competing-risks analysis adjusted for age, sex and CD4 count. Results Between January 2016 and September 2017, 100 patients excluded from STAMP were treated for TB empirically prior to TB screening. After enrolment in STAMP and TB screening, 240/1177 (20.4%) patients received TB treatment, of whom 123 had positive TB tests and 117 were treated empirically. Characteristics were similar among early empirically treated patients and those treated after TB screening. 50% of early empirical TB treatment was based on radiological investigations, 22% on cerebrospinal or pleural fluid testing, and 28% on clinical features alone. Only 11/100 empirically treated patients had subsequent microbiological confirmation. In-hospital mortality was lower in patients with microbiologically-confirmed TB compared to those treated empirically (adjusted sub-distribution HR 0.5, 95% CI 0.3-0.9). Conclusions Empirical TB treatment remains common in severely ill HIV-positive inpatients. These patients may benefit from TB screening using existing rapid diagnostics, both to improve confirmation of TB disease and reduce over-treatment for TB.

Estimating restricted mean survival time and expected life-years lost in the presence of competing risks within flexible parametric survival models

Background Royston-Parmar flexible parametric survival models (FPMs) can be fitted on either the cause-specific hazards or cumulative incidence scale in the presence of competing risks. An advantage of modelling within this framework for competing risks data is the ease at which alternative predictions to the (cause-specific or subdistribution) hazard ratio can be obtained. Restricted mean survival time (RMST), or restricted mean failure time (RMFT) on the mortality scale, is one such measure. This has an attractive interpretation, especially when the proportionality assumption is violated. Compared to similar measures, fewer assumptions are required and it does not require extrapolation. Furthermore, one can easily obtain the expected number of life-years lost, or gained, due to a particular cause of death, which is a further useful prognostic measure as introduced by Andersen. Methods In the presence of competing risks, prediction of RMFT and the expected life-years lost due to a cause of death are presented using Royston-Parmar FPMs. These can be predicted for a specific covariate pattern to facilitate interpretation in observational studies at the individual level, or at the population-level using standardisation to obtain marginal measures. Predictions are illustrated using English colorectal data and are obtained using the Stata post-estimation command, standsurv. Results Reporting such measures facilitate interpretation of a competing risks analysis, particularly when the proportional hazards assumption is not appropriate. Standardisation provides a useful way to obtain marginal estimates to make absolute comparisons between two covariate groups. Predictions can be made at various time-points and presented visually for each cause of death to better understand the overall impact of different covariate groups. Conclusions We describe estimation of RMFT, and expected life-years lost partitioned by each competing cause of death after fitting a single FPM on either the log-cumulative subdistribution, or cause-specific hazards scale. These can be used to facilitate interpretation of a competing risks analysis when the proportionality assumption is in doubt.